Retroviral Infection Dynamics in Maine\u27s Wild Turkeys

Widespread wild turkey reintroductions in the late 1900s have led to increases in population density and geographic distribution across North America. This rapid population expansion has put them into proximity with closely-related wild and domestic avian species, increasing the risks of pathogen transmission. Lymphoproliferative disease virus (LPDV) is an avian oncogenic retrovirus detected in wild turkeys in 2009, and previously known to infect domestic turkeys. Following its initial detection, surveys reported variable LPDV prevalence across eastern North America with most wild turkeys being asymptomatic, however diagnostic cases revealed 10% mortality of LPDV-infected individuals. Given its recent detection, little is known about LPDV ecology, transmission or evolution in wild turkeys. We sought to evaluate (1) an alternative detection method for surveillance, (2) individual risk factors, (3) fitness effects, and (4) the genetic diversity and evolutionary history of LPDV in Maine’s wild turkeys. From 2017–2020, we collected tissues and associated data from 72 hunter-harvested and 627 live-captured wild turkeys, and attached radiotransmitters to a subset of live-captured females to monitor survival and reproduction. We used PCR to estimate the infection prevalence of LPDV (59%) and reticuloendotheliosis virus (REV; 16%), another oncogenic retrovirus. In a sample subset, we used plate agglutination to determine the prevalence of exposure to the bacteria, Mycoplasma gallisepticum (74%) and Salmonella pullorum (3.4%). We found cloacal swabs are a reliable LPDV detection method for live-captured wild turkeys. Sex, age, and season were significant predictors of LPDV infection, with females, adults, and individuals sampled in spring having a higher infection risk. Furthermore, we found both LPDV and REV infection negatively affected individual fitness by reducing clutch size and weekly hen survival rate, respectively. Finally, LPDV in Maine is characterized by high diversity and weak spatial genetic structure, which we hypothesize may be driven by high mutation rates, intrahost pathogen dynamics, and/or the history of human-induced and natural wild turkey movement across the state. Overall, this study provides valuable insights into LPDV infection, transmission, and evolution in wild turkeys, data which will aid in future disease monitoring and risk assessments to evaluate effects of infection on wild turkey population dynamics

Association of Rideshare-Based Transportation Services and Missed Primary Care Appointments: A Clinical Trial

In a pragmatic trial, offering complimentary ridesharing services broadly to Medicaid patients did not reduce rates of missed primary care appointments. The uptake of free rides was low, and rates of missed appointments remained unchanged at 36%. Efforts to reduce missed appointments due to transportation barriers may require more targeted approaches

Capture and Recycle of Industrial CO\u3csub\u3e2\u3c/sub\u3e Emissions Using Mircoalgae

A novel cyclic flow photobioreactor (PBR) for the capture and recycle of CO2 using microalgae was designed and deployed at a coal-fired power plant (Duke Energy’s East Bend Station). The PBR was operated continuously during the period May–September 2015, during which algae productivity of typically 0.1–0.2 g/(L day) was obtained. Maximum CO2 capture efficiency was achieved during peak sunlight hours, the largest recorded CO2 emission reduction corresponding to a value of 81 % (using a sparge time of 5 s/min). On average, CO2 capture efficiency during daylight hours was 44 %. The PBR at East Bend Station also served as a secondary scrubber for NOx and SOx, removing on average 41.5 % of the NOx and 100 % of the SOx from the flue gas. The effect of solar availability and self-shading on a rudimentary digital model of the cyclic flow PBR was examined using Autodesk Ecotect Analysis software. Initial results suggest that this is a promising tool for the optimization of PBR layout with respect to the utilization of available solar radiation

Intraperitoneal Nanotherapy for Metastatic Ovarian Cancer Based on siRNA-Mediated Suppression of DJ-1 Protein Combined with a Low Dose of Cisplatin

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks

Enhanced efficacy and increased long-term toxicity of CNS-directed, AAV-based combination therapy for Krabbe disease

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC) and the progressive accumulation of the toxic metabolite psychosine. We showed previously that central nervous system (CNS)-directed, adeno-associated virus (AAV)2/5-mediated gene therapy synergized with bone marrow transplantation and substrate reduction therapy (SRT) to greatly increase therapeutic efficacy in the murine model of Krabbe disease (Twitcher). However, motor deficits remained largely refractory to treatment. In the current study, we replaced AAV2/5 with an AAV2/9 vector. This single change significantly improved several endpoints primarily associated with motor function. However, nearly all (14/16) of the combination-treated Twitcher mice and all (19/19) of the combination-treated wild-type mice developed hepatocellular carcinoma (HCC). 10 out of 10 tumors analyzed had AAV integrations within the Rian locus. Several animals had additional integrations within or near genes that regulate cell growth or death, are known or potential tumor suppressors, or are associated with poor prognosis in human HCC. Finally, the substrate reduction drug L-cycloserine significantly decreased the level of the pro-apoptotic ceramide 18:0. These data demonstrate the value of AAV-based combination therapy for Krabbe disease. However, they also suggest that other therapies or co-morbidities must be taken into account before AAV-mediated gene therapy is considered for human therapeutic trials

Reducing neuroinflammation by delivery of IL‐10 encoding lentivirus from multiple‐channel bridges

The spinal cord is unable to regenerate after injury largely due to growth‐inhibition by an inflammatory response to the injury that fails to resolve, resulting in secondary damage and cell death. An approach that prevents inhibition by attenuating the inflammatory response and promoting its resolution through the transition of macrophages to anti‐inflammatory phenotypes is essential for the creation of a growth permissive microenvironment. Viral gene delivery to induce the expression of anti‐inflammatory factors provides the potential to provide localized delivery to alter the host inflammatory response. Initially, we investigated the effect of the biomaterial and viral components of the delivery system to influence the extent of cell infiltration and the phenotype of these cells. Bridge implantation reduces antigen‐presenting cell infiltration at day 7, and lentivirus addition to the bridge induces a transient increase in neutrophils in the spinal cord at day 7 and macrophages at day 14. Delivery of a lentivirus encoding IL‐10, an anti‐inflammatory factor that inhibits immune cell activation and polarizes the macrophage population towards anti‐inflammatory phenotypes, reduced neutrophil infiltration at both day 7 and day 28. Though IL‐10 lentivirus did not affect macrophages number, it skewed the macrophage population toward an anti‐inflammatory M2 phenotype and altered macrophage morphology. Additionally, IL‐10 delivery resulted in improved motor function, suggesting reduced secondary damage and increased sparing. Taken together, these results indicate that localized expression of anti‐inflammatory factors, such as IL‐10, can modulate the inflammatory response following spinal cord injury, and may be a key component of a combinatorial approach that targets the multiple barriers to regeneration and functional recovery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134909/1/btm210018.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134909/2/btm210018_am.pd

Towards a Multi-Scale Computer Modeling Workflow for Simulation of Pulmonary Ventilation in Advanced COVID-19

Physics-based multi-scale in silico models offer an excellent opportunity to study the effects of heterogeneous tissue damage on airflow and pressure distributions in COVID-19-afflicted lungs. The main objective of this study is to develop a computational modeling workflow, coupling airflow and tissue mechanics as the first step towards a virtual hypothesis-testing platform for studying airflow and injury mechanics of COVID-19-afflicted lungs. We developed a CT-based modeling approach to simulate the regional changes in lung dynamics associated with heterogeneous subject-specific COVID-19-induced damage patterns in the parenchyma. Furthermore, we investigated the effect of various levels of inflammation in a meso-scale acinar mechanics model on global lung dynamics. Our simulation results showed that as the severity of damage in the patient's right lower, left lower, and to some extent in the right upper lobe increased, ventilation was redistributed to the least injured right middle and left upper lobes. Furthermore, our multi-scale model reasonably simulated a decrease in overall tidal volume as the level of tissue injury and surfactant loss in the meso-scale acinar mechanics model was increased. This study presents a major step towards multi-scale computational modeling workflows capable of simulating the effect of subject-specific heterogenous COVID-19-induced lung damage on ventilation dynamics